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Editorial

Factor Xa inhibitors: a step forward in the treatment of atrial fibrillation?

Ale Algra08 August 2013

Drugs that inhibit the coagulation factors Xa or IIa (thrombin) form a class called new oral anticoagulants (NOACs), which offer an alternative to vitamin K antagonists (VKAs) in the prevention of stroke and systematic embolism in patients with atrial fibrillation. VKAs (e.g. warfarin) have proven efficacy and are recommended by the joint American Heart Association/American Stroke Association guidelines and European Stroke Organisation guidelines for people at moderate-to-high risk of stroke.[1,2] However, dosing of this class of drugs requires titration, and patients need to visit anticoagulation clinics every three to four weeks to have their international normalized ratio (INR) checked. Moreover, VKAs have many interactions with other drugs.

In the August 2013 issue of the Cochrane Database of Systematic Reviews Bruins Slot and Berge report a meta-analysis of 10 trials comparing factor Xa inhibitors with VKAs in patients with atrial fibrillation.[3] The incidence of stroke or systemic embolism was lower with the factor Xa inhibitors, with a number-need-to-treat of approximately 100 patients per year. For major bleeds the data showed heterogeneity: in some analyses the bleeding risk was lower with the new drugs; in other analyses there was no difference that achieved statistical significance. None of the analyses indicated an increased risk of major haemorrhage with factor Xa inhibitors. However, the data clearly showed that intracranial haemorrhage, the most feared bleeding complication, was reduced with the use of factor Xa inhibitors. Also, all-cause death was lower with factor Xa inhibitors (six trials; 881 versus 986 deaths). Among patients with previous stroke or transient ischaemic attack (TIA) factor Xa inhibitors tended to be at least as efficacious (stroke and embolism) and safe (major bleedings) as in all patients with atrial fibrillation (three trials).

The positive findings from these trials have prompted several guideline groups to incorporate the use of NOACs in their recommendations. The European Society of Cardiology now advises that: "where oral anticoagulation is recommended to consider one of the NOACs rather than adjusted-dose VKA (INR 2 to 3) for most patients with non-valvular atrial fibrillation, based on their net clinical benefit".[4] Similar recommendations have been made by the American Heart Association, the American Stroke Association, and the American College of Chest Physicians.[5,6]

Clearly there is broad acceptance of NOACs for treating non-valvular atrial fibrillation, but we may need to be careful in implementing these drugs into clinical practice. First, VKAs may be equally effective and as safe as NOACs in settings with well-organised anticoagulation clinics. A substudy of the RE-LY trial that compared the thrombin inhibitor dabigatran with VKAs showed that relative risks of dabigatran versus VKA depended on the average quality of VKA titration per participating centre: 0.57 for the quartile with the worst titration; 0.50 for the second quartile; 0.69 for the third; and 0.95 for the centres achieving the best titration.[7] There are no such data available for the factor Xa inhibitor trials. Second, in the absence of the need to visit anticoagulation clinics compliance with NOACs may be compromised. Such non-compliance may put patients at risk of thromboembolic events. Also, not all patients consider regular visits to an anticoagulation clinic a nuisance; older people in particular may feel reassured by the periodic 'check-ups'. Third, currently there is no antidote against factor Xa inhibitors. This may be life-threatening in trauma patients or may pose difficulties in patients who need emergency surgery. Fourth, cost-effectiveness analyses show that compared with VKAs NOACS have incremental cost effectiveness ratios (ICERs) of about €8000 to €66,000 per quality-adjusted year of life gained.[8,9] In countries with high-quality anticoagulation clinics ICERs are likely to be higher. Whether factor Xa inhibitors with such ICERs are affordable outside high-income countries is debatable.

We need to be critical followers of the implementation of NOACs. The Health Council of the Netherlands has advised that "the introduction of the NOACs must be accompanied by more detailed research into their safety, effectiveness, and cost-effectiveness".[10] To this end, well-designed phase 4 studies are needed to assess how NOACs perform in 'real life'.

4. Camm AJ, Lip GYH, De Catarina R, Savelieva I, Atar D, Hohnloser SH, et al. 2012 focused update of the ESC Guidelines for the management of atrial fibrillation: an update of the 2010 ESC Guidelines for the management of atrial fibrillation. Developed with the special contribution of the European Heart Rhythm Association. European Heart Journal 2012;33:2719-47. dx.doi.org/10.1093/eurheartj/ehs253

10. Health Council of the Netherlands. New anticoagulants: a well-dosed introduction. The Hague: Health Council of the Netherlands; 2012. Report No.: 2012/07.

Declarations of interest

The author has completed the Unified Competing Interest form at www.icmje.org/coi_disclosure.pdf (available upon request) and declares (1) no receipt of payment or support in kind for any aspect of the article; (2) no financial relationships with any entities that have an interest related to the submitted work; (3) that he was member of the committee of the Health Council of the Netherlands that wrote a report on the introduction of NOACs in the Netherlands, but has no other relationships or activities that could be perceived as having influenced, or giving the appearance of potentially influencing, what was written in the submitted work.